This invention relates to a process for the resolution of N-acyl-DL(.+-.)-phenylalanines to obtain N-acyl-L(+)-phenylalanines which can be hydrolyzed to obtain L(-)-phenylalanine, an intermediate useful in the manufacture of methyl .alpha.-L-aspartyl-L-phenylalanate, a sweetening agent disclosed by Anderson in U.S. Pat. No. 3,901,871.
Heretofore it has been difficult to obtain N-acyl-L(+)-phenylalanines by either asymmetric synthesis or the resolution of N-acyl-DL(.+-.)-phenylalanines. Prior art methods have employed optically active amines. However, since none of the optically active amines has been found to be completely satisfactory, research continues in order to find new optically active amines which will be more satisfactory. The present invention arose out of such research and resulted in the discovery of a more economical and facile process for the resolution of N-acyl-DL(.+-.)-phenylalanines.
In accordance with the present invention, there is provided a process for resolving N-acyl-DL(.+-.)-phenylalanines represented by formula (I) ##STR1## wherein R represents an acyl radical selected from C.sub.1 -C.sub.8 alkanoyl, or benzoyl, comprising:
(A) REACTING ABOUT ONE MOLE OF SAID COMPOUND OF FORMULA (I) with about one mole of D(-)-2-(2,5-dimethylbenzylamino)-1-butanol, represented by formula (II) ##STR2## in an aqueous medium at moderately elevated temperatures to form an essentially saturated solution of a compound represented by formula (III) ##STR3## wherein R is as previously defined,
(B) COOLING SAID ESSENTIALLY SATURATED SOLUTION TO CRYSTALLIZE SAID COMPOUND OF FORMULA (III) and recovering the same,
(C) REACTING SAID COMPOUND OF FORMULA (III) in an aqueous medium with an acid or alkalizing agent to form an optically pure N-acyl-L(+)-phenylalanine represented by formula (IV) ##STR4## and recovering the same.
The preferred compound of formula (I) is N-acetyl-DL(.+-.)phenylalanine.
In accordance with the present invention, there is also provided an alternative process for resolving compounds represented by formula (I) which comprises:
(a) reacting about one mole of said compound of formula (I) with about 0.5 mole of said compound of formula (II) and about 0.5 mole of an alkalizing agent in an aqueous medium at moderately elevated temperatures to form said essentially saturated solution of said compound of formula (III), and following steps (b) and (c) above to recover N-acyl-L(+)-phenylalanine therefrom. The preferred compound of formula (I) is N-acetyl-DL(.+-.)-phenylalanine.
In accordance with the present invention, there are also provided novel compositions of matter represented by formula (III). The preferred species of formula (III) is wherein R is acetyl.
The processes of this invention are advantageous in that the resulting N-acyl-L(+)-phenylanilines are obtained in high yields and very high optical purity, without complicated isolation or recrystallization procedures, for subsequent conversion to the desired L(-)-phenylalanine.